Figure 4.

(See previous page). Ephrin-Eph signaling in embryonic tissues. (A) Multiple activities and cross-talks. Ephrin-Eph receptor interactions typically activate an intracellular signal that induces reorganization of the actin cytoskeleton, including increased actomyosin contraction, leading to retraction. This repulsive activity is thought to be triggered only at high levels of signal. It requires disruption of the ephrin-Eph bonds which connect the 2 cells. This can occur either by endocytosis, or by shedding of the ephrin/Eph extracellular domains by ADAMs proteinases (not shown). It is believed that, under certain condition, in particular under low ephrin-Eph signaling, ephrin-Eph interactions contribute on the contrary to cell-cell adhesion. Note that the exact mechanisms that control adhesive versus repulsive modes are not well understood. Like many other ligand-receptor systems, ephrin-Eph signaling influences other aspects of cell function, such as gene regulation or cell-matrix adhesion. Ephrins and Eph receptors have been found to directly associate with other cell surface components, such as tight junctions. The effect of these interactions is still poorly understood. When co-expressed in the same cell, ephrins and Eph receptors may also establish cross-talks, which are generally considered to lead to signal dampening. (B–E) Examples of ephrin-Eph configurations (top 2 cell rows) and of predicted consequences of loss-of-function on signaling and adhesion within and between tissues (lower rows). (B’–E’) Resulting effect on tissue cohesion/separation. Sorting/separation is symbolized by a gap between the cells. (B) Embryonic tissues express multiple ephrins and Eph receptors. In the simplest cases, they are expressed in fully complementary patterns, such that signaling is exclusively triggered at the tissue interface, where repulsion antagonizes cadherin cell adhesion, resulting in low effective adhesion. Lowering ephrins or Ephs is predicted to decrease repulsion/increase adhesion at the tissue interface and cause their fusion, without major effect on intratissular contacts. Note that the systematic expression of several ephrins and/or several Ephs observed in all systems creates partial - and sometimes even full - redundancy. As a consequence, more than one of these components may need to be removed to inhibit separation. (C) In more complex cases, expression is only partially complementary. Here ephrins and Eph receptors can also interact in one or both tissues. These intracellular interactions can generate repulsion, which may confer to the tissue different physical properties, e.g., lower rigidity and higher migration. (D) Under certain circumstances, Ephrin-Eph intratissular signaling may generate a pro-adhesive activity, effectively increasing tissue cohesion. In this case, ephrin/Eph depletion is predicted to decrease tissue cohesion, and could even in principle result in artificial sorting from the tissue of origin, while concomitant inhibition of repulsion across the boundary could lead the depleted cells to join the opposite tissue. (E) In a situation where intratissular signaling is weakly repulsive (C), partial loss-of-function may switch from repulsive to adhesive mode. Depleted cells may sort into a compact independent population.